Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways
Abstract
1. Introduction
2. Materials and Methods
2.1. Cell Lines and Chemicals
2.2. Cytotoxicity Assay
2.3. DNA Damage Assay
2.4. Cell Cycle Analysis By Flow Cytometry
2.5. Real-Time PCR Analysis
2.6. ELISA (Enzyme-Linked Immunosorbent Assay)
2.7. Immunoblotting Studies
2.8. Immunostaining Studies
2.9. In-silico Docking Analysis
2.10. Statistical Analysis
3. Results
3.1. Lanatoside C Exhibits Cytotoxic Effects Only on Cancer Cells
3.2. Lanatoside C Treatment Induces DNA Damage in Cancer Cell Lines
3.3. Lanatoside C Treatment Increases the Percentage of G2/GM and S Phase Cells in Cancer Cell Lines
3.4. Lanatoside C Inhibits Expression of G2/M Cell Cycle Regulator, MAPK, and PI3K/AKT Pathway Genes
3.5. Lanatoside C Down-Regulates BCL-2 and Up-Regulates BAX to Induce Apoptosis in Cancer Cell Lines
3.6. Lanatoside C Down-Regulates Cell Cycle Checkpoint Protein’s Expression to Exhibit Growth Arrest in Cancer Cell Lines
3.7. Lanatoside C Inhibits MAPK/Wnt, JAK-STAT, and PI3K/AKT/mTOR Pathways
3.8. Immunofluorescence Analysis Based Confirmation of Pathways Attenuated by Lanatoside C
3.9. Molecular Docking Analysis Shows Lanatoside C can Potentially Inhibit Multiple Cancer Targets
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Ethics approval and consent to participate
References
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Cells | Total Length of Comet | Length of Head | Length of Tail | Head DNA (%) | Tail DNA (%) | Tail Movement | Overall Tail Movement (OTM) |
---|---|---|---|---|---|---|---|
MCF7-control | 62 ± 5 | 45 ± 3 | 14 ± 6 | 81 ± 6 | 18 ± 5 | 6. ± 2 | 7 ± 1 |
MCF7-Treated | 252 ± 13 | 89 ± 6 | 162 ± 16 | 19 ± 5 | 80 ± 13 | 427 ± 36 | 261 ± 22 |
A549-control | 112 ± 9 | 94 ± 6 | 18 ± 4 | 92 ± 8 | 9 ± 4 | 3 ± 1 | 6 ± 3 |
A549-Treated | 321 ± 14 | 69 ± 5 | 251 ± 13 | 18 ± 2 | 81 ± 13 | 416 ± 42 | 221 ± 23 |
HepG2-control | 132 ± 8 | 86 ± 7 | 46 ± 6 | 82 ± 12 | 17 ± 3 | 9 ± 4 | 64 ± 1 |
HepG2-Treated | 362 ± 9 | 98 ± 6 | 264 ± 19 | 11 ± 2 | 88 ± 12 | 361 ± 41 | 112 ± 18 |
S.no | PDB ID | Libdock Score | No. of H Bonds | Interacting Residues |
---|---|---|---|---|
1. | 1BG1 | 170.564 | 5 | H bonds: GLY373, GLY421, GLN469, ASN472, LYS551. Interacting residues: ASP369, LEU378, ARG379, GLY380, SER381, ARG382, LYS383, GLU415, GLN416, ARG417, CYS418, ASN420, GLY422, ARG423, ILE431, VAL432, THR433, ASN472, CYS550. |
2. | 1OVE | 140.632 | 8 | H bonds: PRO29, VAL30, VAL38, ARG49, GLY110, ALA111, SER154, ALA157. Interacting residues: ASN26, LEU27, SER28, GLY31, ALA40, ALA51, LYS53, HIS107, LEU108, MET109, ASP112, ASN115, ASN155, LEU156, LEU167, ASP168. |
3. | 1VKX | 124.57 | 7 | H bonds: ARG33, THR52, ASN186, ARG187, GLU193, LYS195, ASP217. Interacting residues: LYS28, ARG30, GLY31, MET32, PRO47, SER51, ASP53, LYS56, THR57, ALA188, PRO189, ALA192, LEU194, LYS218. |
4. | 1WOK | 180.235 | 7 | H bonds: ALA755, ASP756, ALA880, PRO881, THR887, TYR907, HIS937. Interacting residues: TYR710, ASN754, GLN759, GLU763, ASP766, LEU769, ASP770, HIS862, SER864, ASN868, ILE872, GLN875, LEU877, ARG878, ILE879, GLY888, TYR889, MET890, PHE891, GLY894, ILE895, TYR896, LYS903, ALA935, GLU988. |
5. | 2CBZ | 102 | 4 | H bonds: GLN713, GLN714, TRP716, GLN718. Interacting residues: TYR710, PRO712, PHE728, SER689. |
6. | 2E9P | 161.897 | 5 | H bonds: GLU17, PRO98, ASP148, GLY150, GLY204. Interacting residues: GLY18, ALA19, TYR20, LYS38, MET42, LYS43, GLU50, ASN51, ILE52, LYS54, GLU55, GLU91, PHE93, ILE96, GLU97, PRO98, LYS132, GLU134, ASN135, LEU151, ALA200, GLU205, LEU206. |
7. | 2JDO | 51.2917 | 3 | H bonds: GLU323, ASP324, ASP326. Interacting residues: THR306, GLU320, VAL321, ASN325, TYR327, GLY328, ASP388, PRO389, LYS390. |
8. | CDK4 or CYCLIN D1 | 172.401 | 6 | H bonds: GLU11, ILE12, GLY13, LYS35, HIS95, ASP158. Interacting residues: ALA10, VAL14, THR19, VAL20, TYR21, ALA33, LYS35, GLU56, VAL72, PHE93, GLU94, VAL96, ASP97, GLN98, ASP99, ARG101, THR102, GLU144, ASN145, LEU147. |
9 | 2O21 | 116.154 | 5 | H bonds: ASP108, GLU111, VAL130, GLU133, ALA146. Interacting residues: PHE101, TYR105, ARG106, ARG107, PHE109, MET112, VAL131, LEU134, PHE147, GLU149, PHE150, VAL153. |
10 | 3ALN | 102 | 5 | H bonds: ILE108, ARG110, GLU179, MET181, SER233. Interacting residues: GLY109, GLY111, VAL116, ALA129, VAL162, MET178, LEU180, SER182, THR183, SER184, ASP186, LYS187, LYS190, ASN234, LEU236, CYS246, ASP247. |
11 | 3EYG | 87.0358 | 3 | H bonds: SER961, GLY962, ARG1007. Interacting residues: ARG879, ASP880, LEU881, PRO960, SER963, LYS965, GLU966, LYS970, ALA1005, ALA1006, TRP1047, GLU1073, SER1080, SER1083, PRO1084, MET1085, ALA1086. |
12 | 3L54 | 105 | 7 | H bonds: ILE703, ALA704, SER706, ARG707, SER753, LYS809, LUY807. Interacting residues: GLY159, TYR160, GLN705, GLN710, LYS750, ALA754, GLU755, LYS756, LYS808, ASP874, LYS875. |
13 | 3NUP | 97.4948 | 4 | H bonds: THR49, GLU51, GLU52, GLN173. Interacting residues: ARG46, VAL47, GLN48, GLY50, GLY53, MET54, PRO55, PHE172, GLN193, ALA248. |
14 | 3VVH | 137.537 | 8 | H bonds: ALA76, GLY77, ASN78, LYS97, GLU144, MET146, SER194. Interacting residues: LEU74, GLY75, GLY79, GLY80, VAL81, VAL82, ALA95, VAL127, MET143, HIS145, GLY149, SER150, GLN153, LYS192, ASN195, LEU197, CYS207, ASP208. |
15 | 4JSP | 83.6223 | 5 | H bonds: ASP2360, VAL2364, ASP2433, THR2434, THR2436. Interacting residues: PRO2116, THR2164, SER2165, LYS2166, ARG2168, ASP2338, HIS2340, ALA2365, THR2367, ARG2368, GLU2369, LYS2370, GLU2373, TYR2542. |
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Reddy, D.; Kumavath, R.; Ghosh, P.; Barh, D. Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways. Biomolecules 2019, 9, 792. https://doi.org/10.3390/biom9120792
Reddy D, Kumavath R, Ghosh P, Barh D. Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways. Biomolecules. 2019; 9(12):792. https://doi.org/10.3390/biom9120792
Chicago/Turabian StyleReddy, Dhanasekhar, Ranjith Kumavath, Preetam Ghosh, and Debmalya Barh. 2019. "Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways" Biomolecules 9, no. 12: 792. https://doi.org/10.3390/biom9120792
APA StyleReddy, D., Kumavath, R., Ghosh, P., & Barh, D. (2019). Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways. Biomolecules, 9(12), 792. https://doi.org/10.3390/biom9120792